Publications by authors named "Wen-Jun Gao"

71 Publications

Extracorporeal membrane oxygenation for coronavirus disease 2019-associated acute respiratory distress syndrome: Report of two cases and review of the literature.

World J Clin Cases 2021 Mar;9(8):1953-1967

Department of Surgery and Cancer, Imperial College London, London SW10 9NH, United Kingdom.

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2, is a worldwide pandemic. Some COVID-19 patients develop severe acute respiratory distress syndrome and progress to respiratory failure. In such cases, extracorporeal membrane oxygenation (ECMO) treatment is a necessary life-saving procedure.

Case Summary: Two special COVID-19 cases-one full-term pregnant woman and one elderly (72-year-old) man-were treated by veno-venous (VV)-ECMO in the Second People's Hospital of Zhongshan, Zhongshan City, Guangdong Province, China. Both patients had developed refractory hypoxemia shortly after hospital admission, despite conventional support, and were therefore managed by VV-ECMO. Although both experienced multiple ECMO-related complications on top of the COVID-19 disease, their conditions improved gradually. Both patients were weaned successfully from the ECMO therapy. At the time of writing of this report, the woman has recovered completely and been discharged from hospital to home; the man remains on mechanical ventilation, due to respiratory muscle weakness and suspected lung fibrosis. As ECMO itself is associated with various complications, it is very important to understand and treat these complications to achieve optimal outcome.

Conclusion: VV-ECMO can provide sufficient gas exchange for COVID-19 patients with acute respiratory distress syndrome. However, it is crucial to understand and treat ECMO-related complications.
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http://dx.doi.org/10.12998/wjcc.v9.i8.1953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953388PMC
March 2021

From Hyposociability to Hypersociability-The Effects of PSD-95 Deficiency on the Dysfunctional Development of Social Behavior.

Front Behav Neurosci 2021 28;15:618397. Epub 2021 Jan 28.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States.

Abnormal social behavior, including both hypo- and hypersociability, is often observed in neurodevelopmental disorders such as autism spectrum disorders. However, the mechanisms associated with these two distinct social behavior abnormalities remain unknown. Postsynaptic density protein-95 (PSD-95) is a highly abundant scaffolding protein in the excitatory synapses and an essential regulator of synaptic maturation by binding to NMDA and AMPA receptors. The gene encodes PSD-95, and it is a risk gene for hypersocial behavior. Interestingly, PSD-95 knockout mice exhibit hyposociability during adolescence but hypersociability in adulthood. The adolescent hyposociability is accompanied with an NMDAR hyperfunction in the medial prefrontal cortex (mPFC), an essential part of the social brain for control of sociability. The maturation of mPFC development is delayed until young adults. However, how PSD-95 deficiency affects the functional maturation of mPFC and its connection with other social brain regions remains uncharacterized. It is especially unknown how PSD-95 knockout drives the switch of social behavior from hypo- to hyper-sociability during adolescent-to-adult development. We propose an NMDAR-dependent developmental switch of hypo- to hyper-sociability. PSD-95 deficiency disrupts NMDAR-mediated synaptic connectivity of mPFC and social brain during development in an age- and pathway-specific manner. By utilizing the PSD-95 deficiency mouse, the mechanisms contributing to both hypo- and hyper-sociability can be studied in the same model. This will allow us to assess both local and long-range connectivity of mPFC and examine how they are involved in the distinct impairments in social behavior and how changes in these connections may mature over time.
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http://dx.doi.org/10.3389/fnbeh.2021.618397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876227PMC
January 2021

Herb pair of Ephedrae Herba-Armeniacae Semen Amarum alleviates airway injury in asthmatic rats.

J Ethnopharmacol 2021 Apr 24;269:113745. Epub 2020 Dec 24.

School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, 330004, China. Electronic address:

Ethnopharmacological Relevance: Ephedrae Herba (EH, Ephedra sinica Stapf.) and Armeniacae Semen Amarum (ASA, Prunus armeniaca L. var. ansu Maxim.) have been used to treat asthma, cold, fever, and cough in China for thousands of years.

Aim Of The Study: In this study, we aimed to investigate the optimal ratio of EH and ASA compatibility (EAC) to reduce airway injury in asthmatic rats and its possible mechanism.

Methods: Rats were sensitized with a mixture of acetylcholine chloride and histamine bisphosphate 1 h before sensitization by intragastric administration of EAC or dexamethasone or saline for 7 days. Subsequently, the ultrastructure of rat airway epithelial tissue changes, apoptosis of the airway epithelial cells, and the expression of mRNA and protein of EGRF and Bcl-2 were detected.

Results: Transmission electron microscope: EAC (groups C and E) had the most prominent effect on repairing airway epithelial cells' ultrastructural changes in asthmatic rats. TUNEL: dexamethasone and EAC (groups B、C、E and F) inhibited the apoptosis of airway epithelial cells in asthmatic rats (P < 0.05). In situ hybridization: EAC (group E) inhibited the overexpression of EGFR and Bcl-2 mRNA (P < 0.05).Western Blotting: EAC (groups A、B、C、E and F) inhibited the upregulation of airway epithelial EGFR and Bcl-2 protein expression (P < 0.01).

Conclusions: Our findings indicate that EAC can inhibit abnormal changes in airway epithelial structure and apoptosis of airway epithelial cells, thereby alleviating airway injury. In this study, the best combination of EH and ASA to alleviate airway epithelial injury in asthmatic rats was group E (EH: ASA = 8: 4.5).
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http://dx.doi.org/10.1016/j.jep.2020.113745DOI Listing
April 2021

Prepubertal Environment Enrichment Prevents Psychosis-Related Dopamine Dysregulation in a Neurodevelopmental Model for Schizophrenia.

Biol Psychiatry 2021 Feb;89(3):212-214

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2020.11.001DOI Listing
February 2021

The Paraventricular Nucleus of the Thalamus Is an Important Node in the Emotional Processing Network.

Front Behav Neurosci 2020 29;14:598469. Epub 2020 Oct 29.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States.

The paraventricular nucleus of the thalamus (PVT) has for decades been acknowledged to be an important node in the limbic system, but studies of emotional processing generally fail to incorporate it into their investigational framework. Here, we propose that the PVT should be considered as an integral part of the emotional processing network. Through its distinct subregions, cell populations, and connections with other limbic nuclei, the PVT participates in both major features of emotion: arousal and valence. The PVT, particularly the anterior PVT, can through its neuronal activity promote arousal, both as part of the sleep-wake cycle and in response to novel stimuli. It is also involved in reward, being both responsive to rewarding stimuli and itself affecting behavior reflecting reward, likely specific populations of cells distributed throughout its subregions. Similarly, neuronal activity in the PVT contributes to depression-like behavior, through yet undefined subregions. The posterior PVT in particular demonstrates a role in anxiety-like behavior, generally promoting but also inhibiting this behavior. This subregion is also especially responsive to stressors, and it functions to suppress the stress response following chronic stress exposure. In addition to participating in unconditioned or primary emotional responses, the PVT also makes major contributions to conditioned emotional behavior. Neuronal activity in response to a reward-predictive cue can be detected throughout the PVT, and endogenous activity in the posterior PVT strongly predicts approach or seeking behavior. Similarly, neuronal activity during conditioned fear retrieval is detected in the posterior PVT and its activation facilitates the expression of conditioned fear. Much of this involvement of the PVT in arousal and valence has been shown to occur through the same general afferents and efferents, including connections with the hypothalamus, prelimbic and infralimbic cortices, nucleus accumbens, and amygdala, although a detailed functional map of the PVT circuits that control emotional responses remains to be delineated. Thus, while caveats exist and more work is required, the PVT, through its extensive connections with other prominent nuclei in the limbic system, appears to be an integral part of the emotional processing network.
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http://dx.doi.org/10.3389/fnbeh.2020.598469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658442PMC
October 2020

A Subpopulation of Prefrontal Cortical Neurons Is Required for Social Memory.

Biol Psychiatry 2021 Mar 5;89(5):521-531. Epub 2020 Sep 5.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania. Electronic address:

Background: The medial prefrontal cortex (mPFC) is essential for social behaviors, yet whether and how it encodes social memory remains unclear.

Methods: We combined whole-cell patch recording, morphological analysis, optogenetic/chemogenetic manipulation, and the TRAP (targeted recombination in active populations) transgenic mouse tool to study the social-associated neural populations in the mPFC.

Results: Fos-TRAPed prefrontal social-associated neurons are excitatory pyramidal neurons with relatively small soma sizes and thin-tufted apical dendrite. These cells exhibit intrinsic firing features of dopamine D receptor-like neurons, show persisting firing pattern after social investigation, and project dense axons to nucleus accumbens. In behaving TRAP mice, selective inhibition of prefrontal social-associated neurons does not affect social investigation but does impair subsequent social recognition, whereas optogenetic reactivation of their projections to the nucleus accumbens enables recall of a previously encountered but "forgotten" mouse. Moreover, chemogenetic activation of mPFC-to-nucleus accumbens projections ameliorates MK-801-induced social memory impairments.

Conclusions: Our results characterize the electrophysiological and morphological features of social-associated neurons in the mPFC and indicate that these Fos-labeled, social-activated prefrontal neurons are necessary and sufficient for social memory.
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http://dx.doi.org/10.1016/j.biopsych.2020.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867585PMC
March 2021

PSD-95 deficiency alters GABAergic inhibition in the prefrontal cortex.

Neuropharmacology 2020 11 18;179:108277. Epub 2020 Aug 18.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, 19129, USA. Electronic address:

Postsynaptic Density Protein-95 (PSD-95) is a major scaffolding protein in the excitatory synapses in the brain and a critical regulator of synaptic maturation for NMDA and AMPA receptors. PSD-95 deficiency has been linked to cognitive and learning deficits implicated in neurodevelopmental disorders such as autism and schizophrenia. Previous studies have shown that PSD-95 deficiency causes a significant reduction in the excitatory response in the hippocampus. However, little is known about whether PSD-95 deficiency will affect gamma-aminobutyric acid (GABA)ergic inhibitory synapses. Using a PSD-95 transgenic mouse model (PSD-95), we studied how PSD-95 deficiency affects GABA receptor expression and function in the medial prefrontal cortex (mPFC) during adolescence. Our results showed a significant increase in the GABA receptor subunit α1. Correspondingly, there are increases in the frequency and amplitude in spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons in the mPFC of PSD-95 mice, along with a significant increase in evoked IPSCs, leading to a dramatic shift in the excitatory-to-inhibitory balance in PSD-95 deficient mice. Furthermore, PSD-95 deficiency promotes inhibitory synapse function via upregulation and trafficking of NLGN2 and reduced GSK3β activity through tyr-216 phosphorylation. Our study provides novel insights on the effects of GABAergic transmission in the mPFC due to PSD-95 deficiency and its potential link with cognitive and learning deficits associated with neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572776PMC
November 2020

Conditional GSK3β deletion in parvalbumin-expressing interneurons potentiates excitatory synaptic function and learning in adult mice.

Prog Neuropsychopharmacol Biol Psychiatry 2020 06 27;100:109901. Epub 2020 Feb 27.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 W School House Ln, Philadelphia, PA 19129, United States of America. Electronic address:

Glycogen synthase kinase 3β (GSK3β) has gained interest regarding its involvement in psychiatric and neurodegenerative disorders. Recently GSK3 inhibitors were highlighted as promising rescuers of cognitive impairments for a gamut of CNS disorders. Growing evidence supports that fast-spiking parvalbumin (PV) interneurons are critical regulators of cortical computation. Albeit, how excitatory receptors on PV interneurons are regulated and how this affects cognitive function remains unknown. To address these questions, we have generated a novel triple-transgenic conditional mouse with GSK3β genetically deleted from PV interneurons. PV-GSK3β resulted in increased excitability and augmented excitatory synaptic strength in prefrontal PV interneurons. More importantly, these synaptic changes are correlated with accelerated learning with no changes in locomotion and sociability. Our study, for the first time, examined how GSK3β activity affects learning capability via regulation of PV interneurons. This study provides a novel insight into how GSK3β may contribute to disorders afflicted by cognitive deficits.
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http://dx.doi.org/10.1016/j.pnpbp.2020.109901DOI Listing
June 2020

Deletion of Glycogen Synthase Kinase-3β in D Receptor-Positive Neurons Ameliorates Cognitive Impairment via NMDA Receptor-Dependent Synaptic Plasticity.

Biol Psychiatry 2020 04 6;87(8):745-755. Epub 2019 Nov 6.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania. Electronic address:

Background: Cortical dopaminergic systems are critically involved in prefrontal cortex (PFC) functions, especially in working memory and neurodevelopmental disorders such as schizophrenia. GSK-3β (glycogen synthase kinase-3β) is highly associated with cAMP (cyclic adenosine monophosphate)-independent dopamine D receptor (DR)-mediated signaling to affect dopamine-dependent behaviors. However, the mechanisms underlying the GSK-3β modulation of cognitive function via DRs remains unclear.

Methods: This study explored how conditional cell-type-specific ablation of GSK-3β in DR+ neurons (DR-GSK-3β) in the brain affects synaptic function in the medial PFC (mPFC). Both male and female (postnatal days 60-90) mice, including 140 DR, 24 DR, and 38 DISC1 mice, were used.

Results: This study found that NMDA receptor (NMDAR) function was significantly increased in layer V pyramidal neurons in mPFC of DR-GSK-3β mice, along with increased dopamine modulation of NMDAR-mediated current. Consistently, NR2A and NR2B protein levels were elevated in mPFC of DR-GSK-3β mice. This change was accompanied by a significant increase in enrichment of activator histone mark H3K27ac at the promoters of both Grin2a and Grin2b genes. In addition, altered short- and long-term synaptic plasticity, along with an increased spine density in layer V pyramidal neurons, were detected in DR-GSK-3β mice. Indeed, DR-GSK-3β mice also exhibited a resistance of working memory impairment induced by injection of NMDAR antagonist MK-801. Notably, either inhibiting GSK-3β or disrupting the DR-DISC1 complex was able to reverse the mutant DISC1-induced decrease of NMDAR-mediated currents in the mPFC.

Conclusions: This study demonstrates that GSK-3β modulates cognition via DR-DISC1 interaction and epigenetic regulation of NMDAR expression and function.
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http://dx.doi.org/10.1016/j.biopsych.2019.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103512PMC
April 2020

PSD-95 deficiency disrupts PFC-associated function and behavior during neurodevelopment.

Sci Rep 2019 07 1;9(1):9486. Epub 2019 Jul 1.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, 19129, USA.

Postsynaptic density protein-95 (PSD-95) is a major regulator in the maturation of excitatory synapses by interacting and trafficking N-methyl-D-aspartic acid receptors (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid receptors (AMPAR) to the postsynaptic membrane. PSD-95 disruption has recently been associated with neuropsychiatric disorders such as schizophrenia and autism. However, the effects of PSD-95 deficiency on the prefrontal cortex (PFC)-associated functions, including cognition, working memory, and sociability, has yet to be investigated. Using a PSD-95 knockout mouse model (PSD-95), we examined how PSD-95 deficiency affects NMDAR and AMPAR expression and function in the medial prefrontal cortex (mPFC) during juvenile and adolescent periods of development. We found significant increases in total protein levels of NMDAR subunits GluN1, and GluN2B, accompanied by decreases in AMPAR subunit GluA1 during adolescence. Correspondingly, there is a significant increase in NMDAR/AMPAR-mediated current amplitude ratio that progresses from juvenile-to-adolescence. Behaviorally, PSD-95 mice exhibit a lack of sociability, as well as learning and working memory deficits. Together, our data indicate that PSD-95 deficiency disrupts mPFC synaptic function and related behavior at a critical age of development. This study highlights the importance of PSD-95 during neurodevelopment in the mPFC and its potential link in the pathogenesis associated with schizophrenia and/or autism.
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http://dx.doi.org/10.1038/s41598-019-45971-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602948PMC
July 2019

Sonic hedgehog signaling in astrocytes mediates cell type-specific synaptic organization.

Elife 2019 06 13;8. Epub 2019 Jun 13.

Department of Biology, Drexel University, Philadelphia, United States.

Astrocytes have emerged as integral partners with neurons in regulating synapse formation and function, but the mechanisms that mediate these interactions are not well understood. Here, we show that Sonic hedgehog (Shh) signaling in mature astrocytes is required for establishing structural organization and remodeling of cortical synapses in a cell type-specific manner. In the postnatal cortex, Shh signaling is active in a subpopulation of mature astrocytes localized primarily in deep cortical layers. Selective disruption of Shh signaling in astrocytes produces a dramatic increase in synapse number specifically on layer V apical dendrites that emerges during adolescence and persists into adulthood. Dynamic turnover of dendritic spines is impaired in mutant mice and is accompanied by an increase in neuronal excitability and a reduction of the glial-specific, inward-rectifying K channel Kir4.1. These data identify a critical role for Shh signaling in astrocyte-mediated modulation of neuronal activity required for sculpting synapses.
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http://dx.doi.org/10.7554/eLife.45545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629371PMC
June 2019

NMDA receptor hypofunction for schizophrenia revisited: Perspectives from epigenetic mechanisms.

Schizophr Res 2020 03 9;217:60-70. Epub 2019 Apr 9.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, United States of America. Electronic address:

Schizophrenia (SZ) is a neurodevelopmental disorder with cognitive deficits manifesting during early stages of the disease. Evidence suggests that genetic factors in combination with environmental insults lead to complex changes to glutamatergic, GABAergic, and dopaminergic systems. In particular, the N-methyl-d-aspartate receptor (NMDAR), a major glutamate receptor subtype, is implicated in both the disease progression and symptoms of SZ. NMDARs are critical for synaptic plasticity and cortical maturation, as well as learning and memory processes. In fact, any deviation from normal NMDAR expression and function can have devastating consequences. Surprisingly, there is little evidence from human patients that direct mutations of NMDAR genes contribute to SZ. One intriguing hypothesis is that epigenetic changes, which could result from early insults, alter protein expression and contribute to the NMDAR hypofunction found in SZ. Epigenetics is referred to as modifications that alter gene transcription without changing the DNA sequence itself. In this review, we first discuss how epigenetic changes to NMDAR genes could contribute to NMDAR hypofunction. We then explore how NMDAR hypofunction may contribute to epigenetic changes in other proteins or genes that lead to synaptic dysfunction and symptoms in SZ. We argue that NMDAR hypofunction occurs in early stage of the disease, and it may consequentially initiate GABA and dopamine deficits. Therefore, targeting NMDAR dysfunction during the early stages would be a promising avenue for prevention and therapeutic intervention of cognitive and social deficits that remain untreatable. Finally, we discuss potential questions regarding the epigenetic of SZ and future directions for research.
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http://dx.doi.org/10.1016/j.schres.2019.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7258307PMC
March 2020

Selective vulnerability of dorsal raphe-medial prefrontal cortex projection neurons to corticosterone-induced hypofunction.

Eur J Neurosci 2019 07 15;50(1):1712-1726. Epub 2019 Feb 15.

Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, Stratford, New Jersey.

Glucocorticoid hormones and serotonin (5-HT) are strongly associated with the development and treatment of depression, respectively. Glucocorticoids regulate the function of serotonergic neurons in the dorsal raphe nucleus (DR), which are the major source of 5-HT to the forebrain. DR 5-HT neurons are electrophysiologically heterogeneous, though whether this phenotypic variation aligns with specific brain functions or neuropsychiatric disease states is largely unknown. The goal of this work was to determine if chronic exogenous glucocorticoid administration differentially affects the electrophysiological profile of DR neurons implicated in the regulation of emotion versus visual sensation by comparing properties of cells projecting to medial prefrontal cortex (mPFC) versus lateral geniculate nucleus (LGN). Following retrograde tracer injection into mPFC or LGN, male Sprague-Dawley rats received daily injections of corticosterone (CORT) for 21 days, after which whole-cell patch clamp recordings were made from retrogradely labeled DR neurons. CORT-treatment significantly increased the action potential half-width of LGN-projecting DR neurons, but did not significantly affect the firing frequency or excitatory postsynaptic currents of these cells. CORT-treatment significantly reduced the input resistance, evoked firing frequency, and spontaneous excitatory postsynaptic current frequency of mPFC-projecting DR neurons, indicating a concurrent reduction of both intrinsic excitability and excitatory drive. Our results suggest that the serotonergic regulation of cognitive and emotional networks in the mPFC may be more sensitive to the effects of glucocorticoid excess than visual sensory circuits in the LGN and that reduced 5-HT transmission in the mPFC may underlie the association between glucocorticoid excess and depression.
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http://dx.doi.org/10.1111/ejn.14355DOI Listing
July 2019

Neurons in rat orbitofrontal cortex and medial prefrontal cortex exhibit distinct responses in reward and strategy-update in a risk-based decision-making task.

Metab Brain Dis 2019 04 8;34(2):417-429. Epub 2018 Dec 8.

Beijing Key Laboratory of Learning and Cognition, College of Psychology, Capital Normal University, Beijing, 100037, China.

The orbitofrontal cortex (OFC) and the medial prefrontal cortex (mPFC) are known to participate in risk-based decision-making. However, whether neuronal activities of these two brain regions play similar or differential roles during different stages of risk-based decision-making process remains unknown. Here we conducted multi-channel in vivo recordings in the OFC and mPFC simultaneously when rats were performing a gambling task. Rats were trained to update strategy as the task was shifted in two stages. Behavioral testing suggests that rats exhibited different risk preferences and response latencies to food rewards during stage-1 and stage-2. Indeed, the firing patterns and numbers of non-specific neurons and nosepoking-predicting neurons were similar in OFC and mPFC. However, there were no reward-expecting neurons and significantly more reward-excitatory neurons (fired as rats received rewards) in the mPFC. Further analyses suggested that nosepoking-predicting neurons may encode the overall value of reward and strategy, whereas reward-expecting neurons show more intensive firing to a big food reward in the OFC. Nosepoking-predicting neurons in mPFC showed no correlation with decision-making strategy updating, whereas the response of reward-excitatory neurons in mPFC, which were barely observed in OFC, were inhibited during nosepoking, but were enhanced in the post-nosepoking period. These findings indicate that neurons in the OFC and mPFC exhibit distinct responses in decision-making process during reward consumption and strategy updating. Specifically, OFC encodes the overall value of a choice and is thus important for learning and strategy updating, whereas mPFC plays a key role in monitoring and execution of a strategy.
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http://dx.doi.org/10.1007/s11011-018-0360-xDOI Listing
April 2019

The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory.

Neuropharmacology 2018 10 27;141:113-125. Epub 2018 Aug 27.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, 19129, USA. Electronic address:

Epigenetic remodeling contributes to synaptic plasticity via modification of gene expression, which underlies cocaine-induced long-term memory. A prevailing hypothesis in drug addiction is that drugs of abuse rejuvenate developmental machinery to render reward circuitry highly plastic and thus engender drug memories to be highly stable. Identification and reversal of these pathological pathways are therefore critical for cocaine abuse treatment. Previous studies revealed an interesting finding in which the mRNA of histone lysine demethylase, KDM6B, is upregulated in the medial prefrontal cortex (mPFC) during early cocaine withdrawal. However, whether and how it contributes to drug-seeking behavior remain unknown. Here we used a conditioned place preference paradigm to investigate the potential role of KDM6B in drug-associated memory. We found that KDM6B protein levels selectively increased in the mPFC during cocaine withdrawal. Notably, systemic injection of KDM6B inhibitor, GSK-J4, disrupted both reconsolidation of cocaine-conditioned memory and cocaine-primed reinstatement, suggesting dual effects of KDM6B in cocaine reward memory. In addition, we found that NMDAR expression and function were both enhanced during early cocaine withdrawal in mPFC. Injection of GSK-J4 selectively reversed this cocaine-induced increase of NR2A expression and synaptic function, suggesting that mal-adaptation of cocaine-induced synaptic plasticity in mPFC largely underlies KDM6B-mediated cocaine-associated memory. Altogether, these data suggest that KDM6B plays an essential role in cocaine-associated memory, which mainly acts through enhancing cocaine-induced synaptic plasticity in the mPFC. Our findings revealed a novel role of KDM6B in cocaine-associated memory and inhibition of KDM6B is a potential strategy to alleviate drug-seeking behavior.
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http://dx.doi.org/10.1016/j.neuropharm.2018.08.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170674PMC
October 2018

Absence of associative motor learning and impaired time perception in a rare case of complete cerebellar agenesis.

Neuropsychologia 2018 08 18;117:551-557. Epub 2018 Jul 18.

Department of Physiology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China. Electronic address:

Primary cerebellar agenesis (PCA), a brain disease where the cerebellum does not develop, is an extremely rare congenital disease with only eleven living cases reported thus far. Studies of the PCA case will thus provide valuable insights into the necessity of cerebellar development for controlling and modulating cognitive functions of the brain. In this follow-up study, we further investigated the performance of associative learning and time perception of a 26-year-old female complete PCA case. We assessed whether delayed eyeblink conditioning (EBC), which represents prototypical associative motor learning function of the cerebellum, could be partially compensated by the extracerebellar brain regions in complete absence of the cerebellum. We also assessed whether the cerebellum, a critical brain region for millisecond-range interval timing, is essential for perception of the second-range time interval. Twelve neurotypical age-matched individuals were used as controls. We found that although the complete PCA patient had only mild to moderate motor deficits, she was unable to perform the delayed EBC even after 1-week of extensive training. Additionally, the PCA patient also performed poorly during time reproduction experiments in which she overproduced the millisecond-range time intervals, while underproduced the second-range time intervals. The PCA patient also failed to perform the temporal eyeblink conditioning with a 5 s fixed interval as the conditioned stimulus. These results indicate that the cerebellum is indispensable for associative motor learning and involved in timing of sub-second intervals, as well as in the perception of second-range intervals.
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http://dx.doi.org/10.1016/j.neuropsychologia.2018.07.021DOI Listing
August 2018

Cell-Type Specific Development of the Hyperpolarization-Activated Current, Ih, in Prefrontal Cortical Neurons.

Front Synaptic Neurosci 2018 11;10. Epub 2018 May 11.

Department of Neurobiology and Anatomy, College of Medicine, Drexel University, Philadelphia, PA, United States.

H-current, also known as hyperpolarization-activated current (Ih), is an inward current generated by the hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels. Ih plays an essential role in regulating neuronal properties, synaptic integration and plasticity, and synchronous activity in the brain. As these biological factors change across development, the brain undergoes varying levels of vulnerability to disorders like schizophrenia that disrupt prefrontal cortex (PFC)-dependent function. However, developmental changes in Ih in PFC neurons remains untested. Here, we examine Ih in pyramidal neurons vs. gamma-aminobutyric acid (GABA)ergic parvalbumin-expressing (PV+) interneurons in developing mouse PFC. Our findings show that the amplitudes of Ih in these cell types are identical during the juvenile period but differ at later time points. In pyramidal neurons, Ih amplitude significantly increases from juvenile to adolescence and follows a similar trend into adulthood. In contrast, the amplitude of Ih in PV+ interneurons decreases from juvenile to adolescence, and does not change from adolescence to adulthood. Moreover, the kinetics of HCN channels in pyramidal neurons is significantly slower than in PV+ interneurons, with a gradual decrease in pyramidal neurons and a gradual increase in PV+ cells across development. Our study reveals distinct developmental trajectories of Ih in pyramidal neurons and PV+ interneurons. The cell-type specific alteration of Ih during the critical period from juvenile to adolescence reflects the contribution of Ih to the maturation of the PFC and PFC-dependent function. These findings are essential for a better understanding of normal PFC function, and for elucidating Ih's crucial role in the pathophysiology of neurodevelopmental disorders.
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http://dx.doi.org/10.3389/fnsyn.2018.00007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958189PMC
May 2018

PV Interneurons: Critical Regulators of E/I Balance for Prefrontal Cortex-Dependent Behavior and Psychiatric Disorders.

Front Neural Circuits 2018 16;12:37. Epub 2018 May 16.

Department of Neurobiology and Anatomy, College of Medicine, Drexel University, Philadelphia, PA, United States.

Elucidating the prefrontal cortical microcircuit has been challenging, given its role in multiple complex behaviors, including working memory, cognitive flexibility, attention, social interaction and emotional regulation. Additionally, previous methodological limitations made it difficult to parse out the contribution of certain neuronal subpopulations in refining cortical representations. However, growing evidence supports a fundamental role of fast-spiking parvalbumin (PV) GABAergic interneurons in regulating pyramidal neuron activity to drive appropriate behavioral responses. Further, their function is heavily diminished in the prefrontal cortex (PFC) in numerous psychiatric diseases, including schizophrenia and autism. Previous research has demonstrated the importance of the optimal balance of excitation and inhibition (E/I) in cortical circuits in maintaining the efficiency of cortical information processing. Although we are still unraveling the mechanisms of information representation in the PFC, the E/I balance seems to be crucial, as pharmacological, chemogenetic and optogenetic approaches for disrupting E/I balance induce impairments in a range of PFC-dependent behaviors. In this review, we will explore two key hypotheses. First, PV interneurons are powerful regulators of E/I balance in the PFC, and help optimize the representation and processing of supramodal information in PFC. Second, diminishing the function of PV interneurons is sufficient to generate an elaborate symptom sequelae corresponding to those observed in a range of psychiatric diseases. Then, using this framework, we will speculate on whether this circuitry could represent a platform for the development of therapeutic interventions in disorders of PFC function.
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http://dx.doi.org/10.3389/fncir.2018.00037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964203PMC
February 2019

Juvenile treatment with mGluR2/3 agonist prevents schizophrenia-like phenotypes in adult by acting through GSK3β.

Neuropharmacology 2018 07 14;137:359-371. Epub 2018 May 14.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, 19129, PA, USA. Electronic address:

Prodromal memory deficits represent an important marker for the development of schizophrenia (SZ), in which glutamatergic hypofunction occurs in the prefrontal cortex (PFC). The mGluR2/3 agonist LY379268 (LY37) attenuates excitatory N-methyl-D-aspartate receptor (NMDAR)-induced neurotoxicity, a central pathological characteristic of glutamatergic hypofunction. We therefore hypothesized that early treatment with LY37 would rescue cognitive deficits and confer benefits for SZ-like behaviors in adults. To test this, we assessed whether early intervention with LY37 would improve learning outcomes in the Morris Water Maze for rats prenatally exposed to methylazoxymethanol acetate (MAM), a neurodevelopmental SZ model. We found that a medium dose of LY37 prevents learning deficits in MAM rats. These effects were mediated through postsynaptic mGluR2/3 via improving GluN2B-NMDAR function by inhibiting glycogen synthase kinase-3β (GSK3β). Furthermore, dendritic spine loss and learning and memory deficits observed in adult MAM rats were restored by juvenile LY37 treatment, which did not change prefrontal neuronal excitability and glutamatergic synaptic transmission in adult normal rats. Our results provide a mechanism for mGluR2/3 agonists against NMDAR hypofunction, which may prove to be beneficial in the prophylactic treatment of SZ.
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http://dx.doi.org/10.1016/j.neuropharm.2018.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050107PMC
July 2018

Lithium Inhibits GSK3β and Augments GluN2A Receptor Expression in the Prefrontal Cortex.

Front Cell Neurosci 2018 1;12:16. Epub 2018 Feb 1.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States.

Glycogen synthase kinase 3β (GSK3β) is a highly conserved serine/threonine kinase that has been implicated in both psychiatric and neurodegenerative diseases including schizophrenia, bipolar disorder, and Alzheimer's disease; therefore regulating its activity has become an important strategy for treatment of cognitive impairments in these disorders. This study examines the effects of lithium on GSK3β and its interaction with β-catenin and NMDA receptors within the prefrontal cortex. Lithium, a clinically relevant drug commonly prescribed as a mood stabilizer for psychiatric disorders, significantly increased levels of phosphorylated GSK3β serine 9, an inhibitory phosphorylation site, and decreased β-catenin ser33/37/thr41 phosphorylation , indicating GSK3β inhibition and reduced β-catenin degradation. GluN2A subunit levels were concurrently increased following lithium treatment. Similar alterations were also demonstrated lithium administration increased GSK3β serine 9 phosphorylation and GluN2A levels, suggesting a reduced GSK3β activity and augmented GluN2A expression. Correspondingly, we observed that the amplitudes of evoked GluN2A-mediated excitatory postsynaptic currents in mPFC pyramidal neurons were significantly increased following lithium administration. Our data suggest that GSK3β activity negatively regulates GluN2A expression, likely by mediating upstream β-catenin phosphorylation, in prefrontal cortical neurons. Furthermore, our biochemical and electrophysiological experiments demonstrate that lithium mediates a specific increase in GluN2A subunit expression, ultimately augmenting GluN2A-mediated currents in the prefrontal cortex.
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http://dx.doi.org/10.3389/fncel.2018.00016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799274PMC
February 2018

Thalamic Control of Cognition and Social Behavior Via Regulation of Gamma-Aminobutyric Acidergic Signaling and Excitation/Inhibition Balance in the Medial Prefrontal Cortex.

Biol Psychiatry 2018 04 7;83(8):657-669. Epub 2017 Dec 7.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania. Electronic address:

Background: The mediodorsal thalamus plays a critical role in cognition through its extensive innervation of the medial prefrontal cortex (mPFC), but how the two structures cooperate at the single-cell level to generate associated cognitive functions and other mPFC-dependent behaviors remains elusive. Maintaining the proper balance between excitation and inhibition (E/I balance) is of principal importance for organizing cortical activity. Furthermore, the PFC E/I balance has been implicated in successful execution of multiple PFC-dependent behaviors in both animal research and the context of human psychiatric disorders.

Methods: Here, we used a pharmacogenetic strategy to decrease mediodorsal thalamic activity in adult male rats and evaluated the consequences for E/I balance in PFC pyramidal neurons as well as cognition, social interaction, and anxiety.

Results: We found that dampening mediodorsal thalamic activity caused significant reductions in gamma-aminobutyric acidergic signaling and increased E/I balance in the mPFC and was concomitant with abnormalities in these behaviors. Furthermore, by selectively activating parvalbumin interneurons in the mPFC with a novel pharmacogenetic approach, we restored gamma-aminobutyric acidergic signaling and E/I balance as well as ameliorated all behavioral impairments.

Conclusions: These findings underscore the importance of thalamocortical activation of mPFC gamma-aminobutyric acidergic interneurons in a broad range of mPFC-dependent behaviors. Furthermore, they highlight this circuitry as a platform for therapeutic investigation in psychiatric diseases that involve impairments in PFC-dependent behaviors.
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http://dx.doi.org/10.1016/j.biopsych.2017.11.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862785PMC
April 2018

PSD95: A synaptic protein implicated in schizophrenia or autism?

Prog Neuropsychopharmacol Biol Psychiatry 2018 03 21;82:187-194. Epub 2017 Nov 21.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, United States. Electronic address:

The molecular components of the postsynaptic density (PSD) in excitatory synapses of the brain are currently being investigated as one of the major etiologies of neurodevelopmental disorders such as schizophrenia (SCZ) and autism. Postsynaptic density protein-95 (PSD-95) is a major regulator of synaptic maturation by interacting, stabilizing and trafficking N-methyl-d-aspartic acid receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid receptors (AMPARs) to the postsynaptic membrane. Recently, there has been overwhelming evidence that associates PSD-95 disruption with cognitive and learning deficits observed in SCZ and autism. For instance, recent genomic and sequencing studies of psychiatric patients highlight the aberrations at the PSD of glutamatergic synapses that include PSD-95 dysfunction. In animal studies, PSD-95 deficiency shows alterations in NMDA and AMPA-receptor composition and function in specific brain regions that may contribute to phenotypes observed in neuropsychiatric pathologies. In this review, we describe the role of PSD-95 as an essential scaffolding protein during synaptogenesis and neurodevelopment. More specifically, we discuss its interactions with NMDA receptor subunits that potentially affect glutamate transmission, and the formation of silent synapses during critical time points of neurodevelopment. Furthermore, we describe how PSD-95 may alter dendritic spine morphologies, thus regulating synaptic function that influences behavioral phenotypes in SCZ versus autism. Understanding the role of PSD-95 in the neuropathologies of SCZ and autism will give an insight of the cellular and molecular attributes in the disorders, thus providing treatment options in patients affected.
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http://dx.doi.org/10.1016/j.pnpbp.2017.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801047PMC
March 2018

Psychostimulants As Cognitive Enhancers in Adolescents: More Risk than Reward?

Front Public Health 2017 26;5:260. Epub 2017 Sep 26.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States.

Methylphenidate and other psychostimulants, originally developed to treat attention deficit-hyperactivity disorder, are increasingly abused by healthy adolescents and adults seeking an advantage in scholastic performance and work productivity. However, how these drugs may affect cognitive performance, especially in the young brain, remains unclear. Here, we review recent literature and emphasize the risks of abuse of psychostimulants in healthy adolescents and young adults. We conclude that while the desire for cognitive enhancement, particularly with rising costs of education and increasingly competitive nature of scholarship programs, is unlikely to diminish in the near future, it is crucial for the scientific community to thoroughly examine the efficacy and safety of these stimulants in healthy populations across development. The current dearth of knowledge on the dose-response curve, metabolism, and cognitive outcomes in adolescents following methylphenidate or other psychostimulant exposure may be perpetuating a perception of these drugs as "safe" when that might not be true for developing brains.
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http://dx.doi.org/10.3389/fpubh.2017.00260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626934PMC
September 2017

Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia.

J Neurochem 2017 11 5;143(3):320-333. Epub 2017 Sep 5.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.

Schizophrenia (SCZ) is characterized not only by psychosis, but also by working memory and executive functioning deficiencies, processes that rely on the prefrontal cortex (PFC). Because these cognitive impairments emerge prior to psychosis onset, we investigated synaptic function during development in the neurodevelopmental methylazoxymethanol (MAM) model for SCZ. Specifically, we hypothesize that N-methyl-D-aspartate receptor (NMDAR) hypofunction is attributable to reductions in the NR2B subunit through aberrant epigenetic regulation of gene expression, resulting in deficient synaptic physiology and PFC-dependent cognitive dysfunction, a hallmark of SCZ. Using western blot and whole-cell patch-clamp electrophysiology, we found that the levels of synaptic NR2B protein are significantly decreased in juvenile MAM animals, and the function of NMDARs is substantially compromised. Both NMDA-mEPSCs and synaptic NMDA-eEPSCs are significantly reduced in prelimbic PFC (plPFC). This protein loss during the juvenile period is correlated with an aberrant increase in enrichment of the epigenetic transcriptional repressor RE1-silencing transcription factor (REST) and the repressive histone marker H3K27me3 at the Grin2b promoter, as assayed by ChIP-quantitative polymerase chain reaction. Glutamate hypofunction has been a prominent hypothesis in the understanding of SCZ pathology; however, little attention has been given to the NMDAR system in the developing PFC in models for SCZ. Our work is the first to confirm that NMDAR hypofunction is a feature of early postnatal development, with epigenetic hyper-repression of the Grin2b promoter being a contributing factor. The selective loss of NR2B protein and subsequent synaptic dysfunction weakens plPFC function during development and may underlie early cognitive impairments in SCZ models and patients. Read the Editorial Highlight for this article on page 264.
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http://dx.doi.org/10.1111/jnc.14101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653427PMC
November 2017

Juvenile treatment with a novel mGluR2 agonist/mGluR3 antagonist compound, LY395756, reverses learning deficits and cognitive flexibility impairments in adults in a neurodevelopmental model of schizophrenia.

Neurobiol Learn Mem 2017 Apr 16;140:52-61. Epub 2017 Feb 16.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA. Electronic address:

Schizophrenia (SCZ) is a neurodevelopmental psychiatric disorder, in which cognitive function becomes disrupted at early stages of the disease. Although the mechanisms underlying cognitive impairments remain unclear, N-methyl-D-aspartate receptors (NMDAR) hypofunctioning in the prefrontal cortex (PFC) has been implicated. Moreover, cognitive symptoms in SCZ are usually unresponsive to treatment with current antipsychotics and by onset, disruption of the dopamine system, not NMDAR hypofunctioning, dominates the symptoms. Therefore, treating cognitive deficits at an early stage is a realistic approach. In this study, we tested whether an early treatment targeting mGluR2 would be effective in ameliorating cognitive impairments in the methylazoxymethanol acetate (MAM) model of SCZ. We investigated the effects of an mGluR2 agonist/mGluR3 antagonist, LY395756 (LY39), on the NMDAR expression and function in juveniles, as well as cognitive deficits in adult rats after juvenile treatment. We found that gestational MAM exposure induced a significant decrease in total protein levels of the NMDAR subunit, NR2B, and a significant increase of pNR2BTyr1472 in the juvenile rat PFC. Treatment with LY39 in juvenile MAM-exposed rats effectively recovered the disrupted NMDAR expression. Furthermore, a subchronic LY39 treatment in juvenile MAM-exposed rats also alleviated the learning deficits and cognitive flexibility impairments when tested with a cross-maze based set-shifting task in adults. Therefore, our study demonstrates that targeting dysfunctional NMDARs with an mGluR2 agonist during the early stage of SCZ could be an effective strategy in preventing the development and progression in addition to ameliorating cognitive impairments of SCZ.
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http://dx.doi.org/10.1016/j.nlm.2017.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860881PMC
April 2017

A Clinically-Relevant Dose of Methylphenidate Enhances Synaptic Inhibition in the Juvenile Rat Prefrontal Cortex.

J Reward Defic Syndr Addict Sci 2017 26;2(3):69-77. Epub 2017 Jan 26.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.

Methylphenidate (MPH) is perhaps the most commonly prescribed psychoactive substance for young children and adolescents; however, its effects on the immature brain are not well understood. MPH is increasingly abused by adolescents and prescriptions are being issued to increasingly younger children without rigorous psychological testing, raising the potential for misdiagnosis; it is therefore crucial to understand how this drug might impact a healthy, developing brain. Recently, we have shown that a clinically-relevant dose of MPH depresses the activity of pyramidal neurons in the prefrontal cortex of normal juvenile rats, but its effects on inhibitory synaptic transmission remain to be explored. We therefore recorded spontaneous (s), miniature (m), and evoked (e) inhibitory postsynaptic currents (IPSCs) in layer 5 pyramidal neurons in juvenile rat prefrontal cortex. We found a dose-dependent effect of MPH on sIPSC frequency but not amplitude, where 0.3 mg/kg significantly decreased frequency, but 1 mg/kg significantly increased frequency. Moreover, mIPSCs were not affected by either dose of MPH, whereas the amplitudes, as well as paired-pulse ratios and coefficient of variations of evoked IPSCs were significantly increased after MPH treatment, indicating a presynaptic action. Tonic GABA current was also not affected by MPH treatment. Taken together, these results suggest that MPH administration to a healthy juvenile may enhance excitation of GABAergic interneurons; thus shifting the excitation-inhibition balance in the prefrontal cortex towards inhibition, and depressing overall prefrontal cortical activity. Our findings also indicate that the adolescent brain is more sensitive to MPH than previously thought, and dose ranges need to be reconsidered for age as well as size.
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http://dx.doi.org/10.17756/jrdsas.2016-030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136665PMC
January 2017

GSK3β Hyperactivity during an Early Critical Period Impairs Prefrontal Synaptic Plasticity and Induces Lasting Deficits in Spine Morphology and Working Memory.

Neuropsychopharmacology 2016 12 29;41(13):3003-3015. Epub 2016 Jun 29.

Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.

Schizophrenia (SZ) is a neurodevelopmental disorder in which the emergence of cognitive symptoms occurs during early adolescence. Glycogen synthase kinase-3β (GSK3β) plays a critical role in synaptic plasticity during development and is highly implicated in the etiology of SZ. However, how GSK3β activity affects synaptic plasticity and working memory function in the prefrontal cortex (PFC) during development remains unknown. Here we show a GSK3β hyperactivity during the early postnatal period in a neurodevelopmental rat SZ model that receives gestational exposure (E17) to the neurotoxin methylazoxymethanol (MAM). Accompanied with this change, adult MAM rats exhibited a significant decrease in spine density as well as impaired working memory, which was rescued by treatment with a GSK3β inhibitor during the juvenile period. Furthermore, the age-dependent hyperactive GSK3β caused a significant deficit in long-term potentiation (LTP) and facilitated long-term depression (LTD) in PFC pyramidal neurons. Notably, these changes in synaptic plasticity occurred only during the late juvenile period and were efficiently reversed by application of GSK3β inhibitors. Because the balance of LTP and LTD plays a critical role in activity-dependent synaptic stabilization and elimination during cortical development, the transient hyperactive GSK3β likely accounts for the cortical spine loss and PFC-dependent cognitive deficits in adulthood. These results highlight the importance of the postnatal trajectory of GSK3β for spine development and PFC function, and may shed light on the prophylactic treatment of cognitive symptoms in the SZ.
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http://dx.doi.org/10.1038/npp.2016.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101547PMC
December 2016

Disruption of Akt signaling decreases dopamine sensitivity in modulation of inhibitory synaptic transmission in rat prefrontal cortex.

Neuropharmacology 2016 09 6;108:403-14. Epub 2016 May 6.

Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA. Electronic address:

Akt is a serine/threonine kinase, which is dramatically reduced in the prefrontal cortex (PFC) of patients with schizophrenia, and a deficiency in Akt1 results in PFC function abnormalities. Although the importance of Akt in dopamine (DA) transmission is well established, how impaired Akt signaling affects the DA modulation of synaptic transmission in the PFC has not been characterized. Here we show that Akt inhibitors significantly decreased receptor sensitivity to DA by shifting DA modulation of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in prefrontal cortical neurons. Akt inhibition caused a significant decrease in synaptic dopamine D2 receptor (D2R) levels with high-dose DA exposure. In addition, Akt inhibition failed to affect DA modulation of IPSCs after blockade of β-arrestin 2. β-arrestin 2-mediated interaction of clathrin with D2R was enhanced by co-application of a Akt inhibitor and DA. Taken together, the reduced response in DA modulation of inhibitory transmission mainly involved β-arrestin 2-dependent D2R desensitization.
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http://dx.doi.org/10.1016/j.neuropharm.2016.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505175PMC
September 2016

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex.

Brain Res 2016 06 11;1641(Pt B):217-33. Epub 2016 Jan 11.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia PA 19129, United States. Electronic address:

Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System.
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http://dx.doi.org/10.1016/j.brainres.2016.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879059PMC
June 2016

LY395756, an mGluR2 agonist and mGluR3 antagonist, enhances NMDA receptor expression and function in the normal adult rat prefrontal cortex, but fails to improve working memory and reverse MK801-induced working memory impairment.

Exp Neurol 2015 Nov 1;273:190-201. Epub 2015 Sep 1.

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA. Electronic address:

Targeting group II metabotropic glutamate receptors (mGluR2/3) has been proposed to correct the dysfunctional glutamatergic system, particularly NMDA receptor (NMDAR) hypofunction, for treatment of schizophrenia. However, how activation of mGluR2/3 affects NMDAR function in adult animals remains elusive. Here we show the effects of LY395756 (LY39), a compound acting as both an mGluR2 agonist and mGluR3 antagonist, on the NMDAR expression and function of normal adult rat prefrontal cortex (PFC) as well as working memory function in the MK801 model of schizophrenia. We found that in vivo administration of LY39 significantly increased the total protein levels of NMDAR subunits and NR2B phosphorylationin the PFC, along with the amplitude of NMDAR-mediated miniature excitatory postsynaptic currents (mEPSC) in the prefrontal cortical neurons. Moreover, LY39 also significantly increased mTOR and pmTOR expression, but not ERK1/2, Akt, and GSK3β, suggesting an activation of mTOR signaling. Indeed, the mTOR inhibitor rapamycin, and actinomycin-D, a transcription inhibitor, blocked the enhanced effects of LY39 on NMDAR-mEPSCs. These results indicate that LY39 regulates NMDAR expression and function through unidentified mTOR-mediated protein synthesis in the normal adult rat PFC. However, this change is insufficient to affect working memory function in normal animals, nor to reverse the MK801-induced working memory deficit. Our data provide the first evidence of an in vivo effect of a novel compound that acts as both an mGluR2 agonist and mGluR3 antagonist on synaptic NMDAR expression and function in the adult rat PFC, although its effect -on PFC-dependent cognitive function remains to be explored.
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http://dx.doi.org/10.1016/j.expneurol.2015.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845095PMC
November 2015